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Int J Mol Epidemiol Genet 2011;2(1):19-29.

Original Article
Telomere length and variation in telomere biology genes in individuals with
osteosarcoma

Lisa Mirabello, Elliott G. Richards, Linh M. Duong, Kai Yu, Zhaoming Wang, Richard Cawthon, Sonja I. Berndt, Laurie Burdett,
Salma Chowdhury, Kedest Teshome, Chester Douglass, Sharon A. Savage

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA;
Currently with the Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health
Promotion, Centers for Disease Control and Prevention, Atlanta, GA. This work was completed while Ms. Duong was a fellow at
NIH; Core Genotyping Facility, National Cancer Institute, SAIC-Frederick, Gaithersburg, MD, USA; Department of Human
Genetics, University of Utah, 15 N 2030 E, Room 2100, Salt Lake City, UT, USA; Department of Epidemiology, Harvard School of
Public Health, Boston, MA, USA; The National Osteosarcoma Etiology Study Group was represented by Michael A. Simon
(University of Chicago), Marc C. Gebhardt (Massachusetts General Hospital), Mark T. Scarborough (Shands Medical Center,
University of Florida), Steven Gitelis (Rush Presbyterian and St. Lukes Medical Center), Jeffrey J. Eckardt (University of
California at Los Angeles School of Medicine), James R. Neff (Nebraska Health System), Michael J. Joyce (Cleveland Clinic
Foundation), Martin Malawer (Washington Cancer Institute), Michael McGuire, (Creighton University), and H. Clarke Anderson
(University of Kansas Medical Center).

Received October 15, 2010; accepted November 18, 2010; Epub December 20, 2010; published January 1, 2011

Abstract: Osteosarcoma, the most common primary bone tumor, occurs most frequently in adolescents.  Chromosomal
aneuploidy is common in osteosarcoma cells, suggesting underlying chromosomal instability.  Telomeres, located at
chromosome ends, are essential for genomic stability; several studies have suggested that germline telomere length (TL) is
associated with cancer risk.  We hypothesized that TL and/or common genetic variation in telomere biology genes may be
associated with risk of osteosarcoma.  We investigated TL in peripheral blood DNA and 713 single nucleotide polymorphisms
(SNPs) from 39 telomere biology genes in 98 osteosarcoma cases and 69 orthopedic controls.  For the genotyping
component, we added 1363 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.  Short TL was
not associated with osteosarcoma risk overall (OR 1.39, P=0.67), although there was a statistically significant association in
females (OR 4.35, 95% CI 1.20-15.74, P=0.03).  Genotype analyses identified seven SNPs in TERF1 significantly associated
with osteosarcoma risk after Bonferroni correction by gene.  These SNPs were highly linked and associated with a reduced risk
of osteosarcoma (OR 0.48-0.53, P=0.0001-0.0006).  We also investigated associations between TL and telomere gene SNPs
in osteosarcoma cases and orthopedic controls.  Several SNPs were associated with TL prior to Bonferroni correction; one
SNP in NOLA2 and one in MEN1 were marginally non-significant after correction (Padj=0.057 and 0.066, respectively).  This
pilot-study suggests that females with short telomeres may be at increased risk of osteosarcoma, and that SNPs in TERF1 are
inversely associated with osteosarcoma risk.   (IJMEG1010001).

Key words: Osteosarcoma, telomere, single nucleotide polymorphism, epidemiology, telomere length

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Address all correspondence to:
Sharon A. Savage, MD
Clinical Genetics Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute, NIH
6120 Executive Blvd., EPS /7018
Rockville, MD 20892
Phone: (301) 496-5785
Fax: (301) 496-1854
Email:  
savagesh@mail.nih.gov